Multiparticulate granulate comprising insulin

Abstract

The present invention is directed to multiparticulate granulate compositions comprising particles of insulin and particles of an infant nutritional excipient, wherein the multiparticulate granulate is substantially free of layers of insulin and excipient, methods of making thereof, and methods of use thereof.

1 . A multiparticulate granulate comprising particles of insulin and particles of an infant nutritional excipient, wherein the multiparticulate granulate is substantially free of layers of insulin and excipient. 
     
     
         2 . The multiparticulate granulate of  claim 1 , wherein the particles of insulin are dispersed on the particles of the infant nutritional excipient. 
     
     
         3 . The multiparticulate granulate of  claim 1  or  2 , wherein the infant nutritional excipient comprises maltodextrin. 
     
     
         4 . The multiparticulate granulate of  claim 3 , wherein the maltodextrin has a DE value of about 2 to about 20. 
     
     
         5 . The multiparticulate granulate of  claim 4 , wherein the maltodextrin has a DE value of less than about 20. 
     
     
         6 . The multiparticulate granulate of any of  claims 1 - 5 , wherein the multiparticulate granulate has a particle size ranging from about 125 μm to about 1000 μm. 
     
     
         7 . The multiparticulate granulate of any of  claims 1 - 6 , wherein the average particle size ranges from about 200 μm to about 600 μm. 
     
     
         8 . The multiparticulate granulate of any of  claims 1 - 7 , wherein the multiparticulate granulate has a D 10  value ranging from about 5 μm to about 250 μm. 
     
     
         9 . The multiparticulate granulate of any of  claims 1 - 8 , wherein the multiparticulate granulate has a D 50  value ranging from about 150 μm to about 450 μm. 
     
     
         10 . The multiparticulate granulate of any of  claims 1 - 9 , wherein the multiparticulate granulate has a D 90  value ranging from about 500 μm to about 1000 μm. 
     
     
         11 . The multiparticulate granulate of any of  claims 1 - 10 , wherein the particle size distribution of the multiparticulate granulate is monomodal. 
     
     
         12 . The multiparticulate granulate of any of  claims 1 - 11 , wherein the ratio of infant nutritional excipient to insulin ranges from about 2,500:1 to about 750,000:1. 
     
     
         13 . The multiparticulate granulate of any of  claims 1 - 12 , wherein the amount of insulin ranges from about 0.0001 wt. % to about 0.04 wt. %. 
     
     
         14 . The multiparticulate granulate of any of  claims 1 - 13 , wherein the moisture content of the multiparticulate granulate is no more than about 6.5 wt. %. 
     
     
         15 . The multiparticulate granulate of any of  claims 1 - 14 , wherein the insulin comprises no more than about 5 wt. % A-21 desamido human insulin. 
     
     
         16 . The multiparticulate granulate of any of  claims 1 - 15 , wherein the insulin comprises no more than about 15 wt. % total related proteins. 
     
     
         17 . The multiparticulate granulate of any of  claims 1 - 16 , wherein the acceptance value of the multiparticulate granulate is not more than 15 when the content uniformity of the insulin in the multiparticulate granulate is tested using USP <905>. 
     
     
         18 . The multiparticulate granulate of any of  claims 1 - 17 , wherein the bulk uniformity of the multiparticulate granulate is about 90-120% with an RSD of not more than about 5%. 
     
     
         19 . The multiparticulate granulate of any of  claims 1 - 18 , wherein at least 80% of the multiparticulate granulate dissolves within 5 minutes when dispersed in ⅔ by wt. 0.9% saline at 25° C. with vortex mixing at 600 rpm. 
     
     
         20 . The multiparticulate granulate of any of  claims 1 - 19 , wherein the insulin concentration is at least 0.4 IU/g. 
     
     
         21 . The multiparticulate granulate of any of  claims 1 - 20 , wherein the insulin activity of the multiparticulate granulate decreases by no more than about 10% when stored for 12 months at 25° C. (±2° C.) and 60% RH (±5%). 
     
     
         22 . The multiparticulate granulate of any of  claims 1 - 21 , wherein after reconstitution in an aqueous medium, the insulin exhibits no more than 10% loss of insulin as measured by the recovery of insulin after passage through a medical grade polyurethane or silicone nasogastric tube. 
     
     
         23 . The multiparticulate granulate of any of  claims 1 - 21 , wherein after reconstitution in breast milk, the insulin exhibits no more than 10% loss of insulin as measured by the recovery of insulin after passage through a medical grade polyurethane or silicone nasogastric tube. 
     
     
         24 . The multiparticulate granulate of  claim 23 , wherein prior to passage through a medical grade polyurethane or silicone nasogastric tube, the reconstituted solution in breast milk was stored in a plastic syringe for up to 72 h. 
     
     
         25 . The multiparticulate granulate of any of  claims 1 - 24 , wherein after reconstitution in breast milk, the reconstituted solution has an osmolality that is substantially the same as a solution of breast milk alone. 
     
     
         26 . The multiparticulate granulate of  claim 25 , wherein the osmolality of the reconstituted solution is in a range of about 290 mOsmol/kg to about 340 mOsmol/kg. 
     
     
         27 . The multiparticulate granulate of  claim 25 , wherein the osmolality of the reconstituted solution is in a range of about 302 mOsmol/kg to about 330 mOsmol/kg 
     
     
         28 . The multiparticulate granulate of any of  claims 1 - 27 , wherein the multiparticulate granulate has a flow index of 10-30 seconds per 100 g, determined using the method described in European Pharmacopoeia <2.9.16> (10 mm orifice). 
     
     
         29 . A package filled with the multiparticulate granulate of any of  claims 1 - 28 . 
     
     
         30 . The package of  claim 29 , wherein the package comprises a moisture and oxygen barrier. 
     
     
         31 . The package of any of  claims 29 - 30 , wherein the MVTR is less than about 0.1 g/m 2 /24 hr and the OTR is less than about 0.1 cm3/m2/24 hr. 
     
     
         32 . A method of preparing the multiparticulate granulate of any of  claims 1 - 28 , comprising:
 (a) dissolving insulin in acidified water;   (b) adjusting the pH of the resulting insulin solution with a base;   (c) dissolving the resulting insulin solution in aqueous saline to form an insulin solution;   (d) dissolving the infant nutritional excipient into the solution of (c);   (e) granulating particles of the infant nutritional excipient in the presence of the solution of (d), wherein the infant nutritional excipient particles range in size from about 125 μm to about 500 μm; and   (f) drying the granulated particles.   
     
     
         33 . The method of  claim 32 , wherein the method further comprises sieving the dried, granulated particles to provide particles having a particle size ranging from about 125 μm to about 850 μm. 
     
     
         34 . The method of any of  claim 32  or  33 , wherein the dissolved insulin of step (a) has a concentration of about 100 IU/g. 
     
     
         35 . The method of any of  claims 32 - 34 , wherein the insulin of step (a) is dissolved in water having a pH of about 2.4. 
     
     
         36 . The method of  claim 35 , wherein the water having a pH of about 2.4 is an HCl solution. 
     
     
         37 . The method of any of  claims 32 - 36 , wherein the pH after adjustment with base is about 8.25. 
     
     
         38 . The method of any of  claims 32 - 37 , wherein said granulation is carried out at a temperature of no more than about 40° C. for no more than about 10 hours. 
     
     
         39 . The method of any of  claims 32 - 38 , wherein said drying is carried out at a temperature of no more than about 40° C. for no more than about 10 hours. 
     
     
         40 . The method of any of  claims 32 - 39 , wherein said drying is carried out at a temperature of no more than about 37° C. 
     
     
         41 . The method of any of  claims 32 - 40 , wherein after drying, the moisture content of the multiparticulate granulate is no more than about 6.5%. 
     
     
         42 . The method of any of  claims 32 - 41 , wherein the dried granulated particles formed after step (f) do not require size reduction before filling into a unit dose package. 
     
     
         43 . A method of treating enteropathy or intestinal malabsorption in premature infants comprising dissolving the multiparticulate granulate of any of  claims 1 - 28  into a pharmaceutically acceptable aqueous medium to provide a dose of at least about 400 μU of insulin/mL, and administering said dissolved insulin to said premature infant. 
     
     
         44 . The method of  claim 43 , wherein the dose is 400 μU of insulin/mL or 2000 μU of insulin/mL. 
     
     
         45 . The method of any of  claims 43 - 44 , wherein said pharmaceutically acceptable aqueous medium is selected from the group consisting of normal saline, half-normal saline, infant formula, or breast milk. 
     
     
         46 . A method of treating neonatal short bowel syndrome in infants comprising dissolving the multiparticulate granulated of any of  claims 1 - 28  into a pharmaceutically acceptable aqueous medium to provide a dose of at least about 4 U of insulin/kg body weight of the infant, and administering said dissolved insulin to said premature infant. 
     
     
         47 . The method of  claim 46 , wherein the dose is 4 U of insulin/kg body weight of the infant or 8 U of insulin/kg body weight of the infant. 
     
     
         48 . The method of any of  claims 46 - 47 , wherein said pharmaceutically acceptable aqueous medium is selected from the group consisting of normal saline, half-normal saline, infant formula, or breast milk. 
     
     
         49 . The method of any of  claims 43 - 48 , wherein said pharmaceutically acceptable aqueous medium is infant formula or breast milk.